MAPK10

protein-coding

mitogen-activated protein kinase 10, the group of Mitogen-activated protein kinases|MicroRNA protein coding host genes

Gene summary

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as integration points for multiple biochemical signals, and thus are involved in a wide variety of cellular processes, such as proliferation, differentiation, transcription regulation and development. This kinase is specifically expressed in a subset of neurons in the nervous system, and is activated by threonine and tyrosine phosphorylation. Targeted deletion of this gene in mice suggests that it may have a role in stress-induced neuronal apoptosis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

Previous symbols:

PRKM10

MANE transcript

NM_138982.4

Inheritance

ClinVar variants

U:27B:11

Top phenotype

Epileptic encephalopathy, Lennox-Gastaut type

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr4:85,990,007-86,594,625

External References & Databases

Ensembl (ENSG00000109339)

Transcript & Mutation Effects

hg38 • Region Span ~604.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Lennox-Gastaut syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0016532

Submitter: G2P

Clinical Genomic Database (CGD)

Epileptic encephalopathy, Lennox-Gastaut typeAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 16249883; 23329067

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAPK10 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 27

not providedTotal: 9

MAPK10-related disorderTotal: 6

Prostate cancerTotal: 1

Epileptic encephalopathy with cognitive deficitTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138982.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	7 clinvar	3 clinvar	11
missense			23 clinvar	1 clinvar		24
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	27	8	3	38

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 178 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138982.4	RefSeq	NP_620448.1	12	MANE Select
ENST00000641462.2	Ensembl	ENSP00000493435.1	12	MANE Select
NM_001318067.1	RefSeq	NP_001304996.1	12	Standard
NM_001318068.1	RefSeq	NP_001304997.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mapk10	Danio rerio	Structure: enteric neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

mapk10

Danio rerio

Structure: enteric neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inflammatory mediator regulation of TRP channels - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Relaxin signaling pathway - Homo sapiens (human)
Adipocytokine signaling pathway - Homo sapiens (human)
Fc epsilon RI signaling pathway - Homo sapiens (human)

Biological Process

activation of MAPK activity
protein phosphorylation
signal transduction
JNK cascade
JUN phosphorylation

Molecular Function

JUN kinase activity
MAP kinase activity
MAP kinase kinase activity
protein binding
ATP binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359221
Coding exons: 12
Length: 579009
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.04	121	259	0.468	0.0000132	3076
Missense (PolyPhen)		22	90.659	0.24267		1105
Synonymous	0.227	92	94.8	0.970	0.00000515	835
Loss of Function	3.57	6	25.4	0.236	0.00000114	327

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress- activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the amyloid-beta precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons. Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the photic regulation of the circadian clock (PubMed:22441692). {ECO:0000269|PubMed:11718727, ECO:0000269|PubMed:22441692}.;
Disease: DISEASE: Note=A chromosomal aberration involving MAPK10 has been found in a single patient with pharmacoresistant epileptic encephalopathy. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. {ECO:0000269|PubMed:16249883}.;

Recessive Scores

pRec: 0.624

Intolerance Scores

LoFtool: 0.233
RVIS EVS: -0.45
RVIS percentile EVS: 24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium